Targeted at learning about the pathogenesis of inflammatory eye diseases grouped under the term "uveitis", this project in FY 1992 focused mainly on learning about ocular antigens that induce experimental autoimmune uveoretinitis (EAU), an animal model for uveitis in man, and on procedures that modulate this disease. Major achievements are three: (1) We found that the substitution of certain residues of the bovine IRBP peptide 1181-1191 eliminated its high uveitogenicity. The corresponding sequence of the rat IRBP differs from the bovine sequence by two residues and was found to be completely nonuveitogenic. (2) To investigate mechanisms of specific unresponsiveness toward uveitogenic peptides, we developed an in vitro system in which lymphocytes sensitized toward peptide 1181-1191 are rendered unresponsive. We have defined the process to be highly specific and to involve active metabolic events. (3) We have examined three procedures aimed at inhibiting the immunopathogenic process of EAU: (a) EUA induced in rats by IRBP peptide 1181-1191 was completely inhibited when this peptide was coinjected with a competing peptide, A183, an analog of a peptide derived from a Mycobacterium tuberculosis protein. On the other hand, nonuveitogenic analogs of peptide 1181-1191 were inactive in this system. (b) The procedure of oral tolerance, shown in another project to inhibit S-antigen-induced EAU effectively, also was found to modulate EAU induced by the small peptide 1181-1191. Furthermore, using analogs of peptide 1181-1191 we have shown that oral tolerance is highly specific: Only cross-reactive analogs were effective. (c) We have examined a new immunosuppressive drug, mycophenolate mofetil (MM), for inhibition of EAU. MM completely inhibited both actively induced and adoptively transferred EAU when given at doses that had no apparent side effects.